This project addresses Broad Challenge Area 04-Clinical Research and Specific Challenge Topic 04-AI-101*- Develop novel methods and address key questions in mucosal immunology. Sexually transmitted diseases (STDs) cause high morbidity and mortality, and thus result in a major disease burden worldwide. New preventive vaccines against HPV have proven that protective immunity can be mounted;but challenges in curing HPV-associated cancer and other major STDs associated with HIV, HSV, Chlamydia, and other bacteria still remain. The female genital tract is a major infection site and a route for the transmission of pathogens. Therefore, vaccines that induce potent mucosal immunity in the vagina have a high potential for the prevention and treatment of STDs. The vagina is a promising site for mucosal vaccine administration. The key question is: how can we establish potent mucosal immunity against STDs in the vagina? Simply delivering vaccines to the vagina may not induce potent mucosal immunity. Dendritic cells (DCs) are major antigen presenting cells (APCs) for both cellular and humoral immunity, but different subsets of DCs have distinct functions in inducing and regulating immune responses. Thus, knowledge of the subsets of vaginal APCs will be crucial for designing mucosal vaccines that induce potent mucosal immunity in the vagina. However, the immunology of the human vagina is poorly understood. To fill the dual gaps of the lack of experts and limited knowledge, here we initiate a comprehensive study for harnessing the immunology of human vagina. This study is greatly facilitated by 1) procuring sufficient tissue samples from Baylor University Medical Center, 2) taking advantage of using the established knowledge in human skin DC subsets at the Baylor Institute for Immunology Research (BIIR), and 3) employing a systems biology approach for a comprehensive analysis of immune responses. At the end of this study, we will be able to provide knowledge in three key areas for developing mucosal vaccines against STDs: 1) The subsets of APCs that can elicit optimal quantity and quality of mucosal immunity in the vagina, 2) APC subset-specific surface receptors and activators for: a) delivering vaccines to appropriate subsets of APCs and b) activating the correct APC subsets, and 3) In situ experimental systems explored in this study will bring key insights of in vivo human immunology necessary for developing vaccines. At BIIR, we have developed a technology platform for targeting antigens directly to human DC subsets via anti-DC receptor antibody vehicles;and this work will permit informed decisions for choosing the targeting receptors and adjuvants best suited to elicit potent and sustained mucosal immunity. Importantly, this proposal fulfills the premises of the challenge funding opportunities by 1) developing novel methods and addressing key questions in human mucosal immunology, 2) generating a broad and major impact on health improvement worldwide by providing key knowledge for developing vaccines against a wide range of STD, 3) making a fundamental contribution in human immunology, and 4) preserving and creating jobs and training for highly skilled scientists. PUBLIC HEALTH RELEVANCE: This work will address the challenge in human mucosal immunology. It will have a broad impact in science and health as it will provide fundamental knowledge in the immunology of the human genital tract, particularly the vagina, which is a major site of infection and transmission of sexually-transmitted diseases (STDs). The results of this study will have immediate implications for the rational design and development of safe and effective vaccines against STDs. Importantly, this work will allow preservation and creation of jobs. 1